Saxenda® in Obese or Overweight Patients With Stable Bipolar Disorder (Investigator Initiated)

BACKGROUND AND SIGNIFICANCE:

Obesity is common among persons with severe mental illness (SMI), especially those with
bipolar disorder (BP) (1-5). It is estimated that 45-55% of people with SMI are obese, making
obesity 1.5-2 times more common among those with SMI than among the general population.
Indeed, in a recent pragmatic lithium trial conducted in BP, 69% of the subjects were
overweight or obese. Although the precise mechanism underlying the relationship between
obesity and SMI is unknown, it is thought to be multifactorial, involving genetic factors,
intrinsic features of SMI (e.g., overeating, poor dietary choices, sedentary lifestyle, and
sleep dysregulation), and the weight-gaining effects of most of the psychotropic medication
used to treat SMI.

Importantly, obesity is thought to contribute to the well-documented elevated mortality from
cardiovascular disease (CVD) among those with BP. Thus, weight reduction in obese people with
BP might be important for reducing their morbidity and mortality from CVD and other
obesity-related conditions (e.g., diabetes and metabolic syndrome). Conversely, the presence
of obesity in patients with BP is associated with a more severe course of illness , a lower
health-related quality of life (18), reductions in brain gray and white volumes (19, 20), and
non-adherence with antipsychotic medications . Indeed, it has been hypothesized that
successful treatment of obesity in those with BP might benefit mental as well as physical
health. It is thus imperative that obesity be a focus of treatment in those with BP.

Comprehensive behavioral weight management programs have shown some effectiveness for obesity
in patients with SMI, but the weight loss is modest at best and such programs are difficult
to implement and not widely available. Several medications have been shown to mitigate
psychotropic-induced weight gain, particularly metformin and topiramate, but many patients
either do not respond to these agents or are unable to tolerate them. Importantly, the
efficacy and safety of newly available weight-loss agents have not been evaluated in people
with SMI.

In December 2014, the U.S. Food and Drug Administration approved liraglutide [rDNA origin] 3
mg/day subcutaneous [sc] injection) (Saxenda®) as a treatment option for chronic weight
management in individuals with obesity. The drug is approved for use in adults with a body
mass index (BMI) of 30 or greater (obesity) or adults with a BMI of 27 or greater
(overweight) who have at least one weight-related comorbid condition such as hypertension,
type 2 diabetes, or dyslipidemia, in combination with reduced-calorie diet and increased
physical activity. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist.
Saxenda® and Victoza® contain the same active ingredient (liraglutide) at different doses (3
mg and 1.8 mg, respectively). However, unlike Victoza®, Saxenda® is not indicated for the
treatment of type 2 diabetes, as the safety and efficacy of Saxenda® for the treatment of
diabetes has not been established.

Several lines of evidence suggest that liraglutide 3.0 mg sc injection (Saxenda®), in
combination with a reduced-calorie diet and increased physical activity, would be a useful
weight-loss treatment for patients with BP who are overweight or obese.

First, GLP-1 is a gut/brain peptide that is secreted from intestinal mucosal enteroendocrine
L cells in response and in proportion to nutrient stimulation of the gut, and that suppresses
food intake by acting on receptors in key areas of the brain that regulate energy balance
(e.g., hypothalamus and hindbrain) (34-37). In humans, administration of GLP-1 reduces food
intake and increases satiation in a dose-dependent manner (37). Obesity in people with BP, as
well as psychotropic-induced weight gain, are thought to be due to in part to increased food
intake (2). It is thus possible that liraglutide 3.0 mg sc injection will decrease food
intake in obese patients with BP, thereby reducing body weight.

Second, preliminary preclinical and clinical findings suggest liraglutide 3.0 mg sc injection
may be effective for antipsychotic-induced weight gain and antipsychotic-induced obesity
(38). Thus, liraglutide has been shown to produce weight loss in animal models of
olanzapine-induced weight gain. In one of these studies, liraglutide also produced
antidepressant-like effects. (Indeed, other animal studies suggest that liraglutide may have
antipsychotic properties. In the only published case of liraglutide use in a patient with
SMI, an obese (BMI 33.5=mg/kg2) 60-year-old woman with schizophrenia treated with clozapine,
liraglutide (1.8mg/day) produced a sustained weight loss of 7.7 kg (an 8.7% body weight
reduction) over two years. Liraglutide was well tolerated and there were no psychiatric
adverse events (i.e., the patient's schizophrenia remained stable). At our own center, we
have treated a 32-year-old woman with schizoaffective disorder, bipolar type and obesity
(BMI=36 mg/kg2) receiving one depot and two oral antipsychotics with liraglutide 3.0 mg sc
injection and, to date, she has lost 7.5 kg (an 8.3% body weight reduction) over a 4-month
period. She reports the liraglutide 3.0 mg sc injection has reduced her hunger and improved
her satiety. She has tolerated liraglutide 3.0 mg sc injection well and has had no
difficulties with giving herself the injections, her psychological symptoms have remained
stable, and there have been no adverse psychiatric effects. Indeed, her mild tardive
dyskinesia is much improved

Third, relative to other weight loss agents, liraglutide 3.0 mg sc injection has a favorable
psychiatric and cardiovascular adverse event profile. Regarding psychiatric events, in the
pivotal liraglutide 3.0 mg sc injection clinical trials, 6 (0.2%) of 3384 liraglutide 3.0 mg
sc injection-treated patients had suicidal ideation (one of these individuals made a suicide
attempt) compared with none of the 1941 placebo-treated patients. Additionally, 2.4% of
liraglutide 3.0 mg sc injection recipients had insomnia and 2.0% had anxiety, compared with
1.7% and 1.6 %, respectively, of placebo recipients. Conversely, lorcaserin (Belviq®) was
associated with euphoria (0.2% vs < 0.1% for placebo) and is contraindicated in patient's
receiving serotonergic medications (and many psychotropics enhance serotonin function).
Phenermine/topiramate combination (Qsymia®), at the highest approved dose, was associated
with insomnia (11.1% vs 5.8% for placebo), depression/mood problems (7.6% vs 3.4% for
placebo), and anxiety (7.9% vs 2.6% for placebo). Additionally, one of the components of
Qsymia®, topiramate, is associated with suicidality. Bupropion/naltrexone combination
(Contrave®), at the highest recommended dose, was associated insomnia (9.2% vs 5.9% for
placebo), anxiety (4.2% vs 2.8% for placebo), and irritability (2.6% vs 1.8% for placebo).
Moreover, there are reports of components of these latter medications (e.g., phentermine and
bupropion) causing severe adverse psychiatric events, such as mania and psychosis. Taken
together, these findings suggest that liraglutide 3.0 mg sc injection may be the least likely
of these weight management medications to exacerbate psychiatric symptoms in people with BP.
Indeed, GLP-1 analogues have been reported to produce enhanced well-being in patients with
diabetes.

Taken together these data support the hypothesis that liraglutide 3.0 mg sc injection will
reduce body weight and improve metabolic variables in obese or overweight patients with BP
without worsening psychiatric symptoms. We predict that liraglutide 3.0 mg sc injection will
display greater efficacy as compared to placebo in decreasing body weight in patients with BP
who are obese or overweight. To prove this hypothesis, we will conduct a single-center,
randomized, placebo-controlled, double-blind, parallel-group, 2-arm clinical trial of
liraglutide 3.0 mg sc injection in 60 obese or overweight outpatients with stable BP. We have
chosen BP rather than another SMI because it is the most common SMI (more common than
schizophrenia or schizoaffective disorder) and has a particularly strong association with
obesity.

RESEARCH DESIGN AND METHODS

Study hypothesis (es):

The central research question is whether liraglutide 3.0 mg sc injection is efficacious for
reducing body weight in obese or overweight patients with BP. We hypothesize that liraglutide
3.0 mg sc injection will be an efficacious, safe, and well tolerated treatment for weight
loss in obese or overweight patients with stable BP. We predict that liraglutide 3.0 mg sc
injection will display greater efficacy as compared to placebo in decreasing body weight in
patients with BP who are overweight or obese without increasing psychiatric adverse events.
We also predict that liraglutide 3.0 mg sc injection will produce a greater percentage of
patients who lose ≥ 5% of baseline body weight, and improve BMI, waist circumference, fasting
lipid and glucose levels, HgA1c levels, and measures of eating psychopathology.

Endpoints:

The primary endpoint will be the percent change in body weight from Baseline (Week 0) to week
40/Early Termination (ET) (see Table 1 for a schedule of assessments). Secondary endpoints
will include proportion of participants who lose ≥ 5% of baseline body weight, and change
from baseline in body weight (kg), BMI, waist circumference, and metabolic variables (fasting
lipids and glucose, and HgA1c levels). Exploratory secondary endpoints will be change from
baseline in eating psychopathology, assessed with the Three Factor Eating Questionnaire
(TFEQ) and Binge Eating Scale (BES). Safety endpoints assessed at each study visit will be
mental status examination, clinically-administered scales that assess psychopathology (CGI-BP
scale [both Severity and Improvement subscales], YMRS, MADRS, and CSSRS), vital signs, and
adverse events determined by clinical interview. Laboratory tests and 12-lead
electrocardiograms (ECGs) will be obtained at Screening, week 8, week 16/ET, and week 40/ET.
Compliance will be assessed at each visit with inspection of returned multi-dose pens.
Potential interactions between liraglutide and psychiatric medications will be monitored and
recorded on the Potential Drug Interaction form (see p. 28).

Study type:

This is a single-center, randomized, placebo-controlled, double-blind, two-arm,
parallel-group, fixed-dose efficacy and safety study with 3 phases: a 3-27 day Screening
period; a 40-week randomized, double-blind Treatment period (4 weeks of dose titration and 36
weeks of dose maintenance); and a 1-week Follow-up (drug discontinuation) period. The purpose
of the 40-week Blinded Treatment phase is to establish the efficacy of liraglutide 3.0 mg sc
injection for weight loss in obese patients with stable BP.

Study population:

We expect to screen about 90 subjects in order to randomize 60 subjects in a 1:1 ratio to
drug or placebo. Patients will be recruited from the Lindner Center of HOPE, Mason, OH, a
University of Cincinnati College of Medicine Affiliate. Patients will be recruited by
clinician referral and advertisement.

Participants will include 60 outpatients with a DSM-5 diagnosis of BP that is stable, who are
obese or overweight with at least one weight-related comorbidity, and who have been receiving
a stable psychotropic regimen for the past three months. The weight-related comorbidities to
be included will be hypertension, type 2 diabetes, and dyslipidemia. Allowed psychotropic
medications for BP will include mood stabilizers (lithium, valproate, and lamotrigine),
antipsychotics (asenapine, aripiprazole, cariprazine, chlorpromazine, clozapine, haloperidol,
loxapine, olanzapine, paliperidone, perphenazine, quetiapine, resperidone, thiothixene,
trifluoperazine, or ziprasidone), antidepressants, and anxiolytics (benzodiazepines,
gabapentin or pregabalin, and buspirone). Stable BP will be operationally defined as a
CGI-BP-Severity score of 1through 3 (1= normal, not at all; 2= borderline mentally ill;
3=mildly ill); a YMRS score ≤12; a MADRS score ≤19, and the absence of clinically significant
suicidality and psychosis. Participants must be 18 through 65 years of age, be able to
provide informed consent, and if female, be postmenopausal, surgically incapable of
childbearing, or practicing a medically acceptable method(s) of contraception (e.g., hormonal
method, intrauterine device) for at least 1 month prior to study entry and throughout the
study. Exclusion criteria include subjects with a lifetime DSM-5 Axis I diagnosis of
dementia, a psychotic or depressive disorder, or a substance use disorder within the past
three months; those with clinically significant psychotic features or suicidal ideation;
those with serious or unstable general medical illnesses; those with a personal or family
history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2; those
who are allergic to or who have demonstrated hypersensitivity to liraglutide 3.0 mg sc
injection or any of its components; and females who are pregnant, nursing, or intend to
become pregnant. Specific entry criteria are listed below.

Inclusion Criteria:

1. Men and women, ages of 18-65 years, inclusive.

2. Participants will have a DSM-5 bipolar disorder that is clinically stable.

3. Participants will have received a stable major psychotropic drug regimen (except for
minor dosage adjustments) for at least 3 months prior study entry. Major psychotropic
drugs are antipsychotics, mood stabilizers, and antidepressants. Subjects may have had
changes in adjunctive benzodiazepines and hypnotic agents.

4. Participants will be obese (defined as a BMI ≥ 30 mg/kg2) or overweight (defined as
BMI ≥ 27 kg/m2) with at least one weight-related comorbidity, such as hypertension,
type 2 diabetes, or dyslipidemia.

5 Participants in treatment for a weight-related comorbidity (hypertension, type 2
diabetes, and/or dyslipidemia) must be on a stable and allowed treatment regimen for that
condition for at least 3 months prior to study enrollment.

6 Participants will be able to provide informed consent before any trial-related
activities.

Exclusion Criteria:

1. Women who are pregnant, lactating, or of childbearing potential who are not using
adequate contraceptive measures. The following are considered to be adequate methods
of birth control: 1.Intrauterine device (IUD); 2. Barrier protection; 3.Contraceptive
implantation system (Norplant); 4.Oral contraceptive pills; 5. A surgically sterile
partner; and 6. Abstinence. Women who are > 2 years post-menopausal or
surgically-sterile are not considered of childbearing potential. All female
participants will have a negative pregnancy test prior to randomization.

2. Participants who have made a suicide attempt in the last 10 years, who are displaying
clinically significant psychotic features, suicidality, or homicidality on mental
status examination, or who have suicidal ideation or behavior as assessed with the
C-SSRS.

3. Participants who are receiving behavioral weight loss treatment (BWLT) (e.g., Weight
Watchers) that was begun within the 3 months before study entry. Participants who are
receiving BWLT that was started 3 months prior to the beginning of the study will be
allowed to continue to receive their BWLT during the trial only if they have had no
weight loss in the past 3 months and they agree to not make any changes in the
frequency or nature of their BWLT during the course of the drug trial.

4. A DSM-5 diagnosis of a substance-related or addictive disorder (except a
tobacco-related disorder) within the 3 months prior to enrollment.

5. A DSM-5 diagnosis of dementia, a psychotic disorder, or a depressive disorder.

6. History of any psychiatric disorder which might interfere with a diagnostic
assessment, treatment, or compliance.

7. Clinically unstable medical disease, including cardiovascular, hepatic, renal,
gastrointestinal, pulmonary, neurological, metabolic, endocrine, or other systemic
disease. Clinically stable hypertension, type 2 diabetes, or dyslipidemia are not
exclusionary.

8. Have a history of a structural cardiac abnormality, valvular cardiac disease,
cardiomyopathy, serious heart rhythm abnormality, coronary artery disease, congestive
heart failure, stroke, or other serious cardiovascular problem.

9. Have an ECG with significant arrhythmias or conduction abnormalities, which in the
opinion of the physician investigator preclude study participation.

10. Have clinically relevant abnormal laboratory results.

11. Participants requiring treatment with any drug which might interact adversely with or
obscure the action of the study medication. This includes anti-obesity drugs,
psychostimulants, modafinil or armodafinil, topiramate or zonisamide, and
antipsychotics. Participants receiving metformin at a stable dose for ≥ 3 months can
be included.

12. Participants receiving GLP-1 based therapies, sodium-glucose co-transporter 2
inhibitors (SGLT2s), thiazolidinediones, sulfonylureas, or insulin.

13. Participants with a personal or family history of medullary thyroid carcinoma or
Multiple Endocrine Neoplasia syndrome type 2.

14. Participants who have received any investigational medication within three months
prior to randomization.

15. Participants previously screen-failed or randomised to participate in this trial.

16. Participants who have a known or suspected allergy to liraglutide 3.0 mg sc injection,
its constituents, or related products.

17. Participants with a urine drug screen positive for a drug that, in the opinion of the
investigator, is being abused.

18. Participants with a past medical history of pancreatitis.

19. Participants who had received any investigational drug within 3 months prior to this
trial.

20. Participants who require bariatric surgery or are anticipated to require it during the
course of the trial. If such surgery becomes warranted during the study, such patients
will be excluded from the primary endpoint analysis.